Mitochondrial GTP metabolism acts through mitochondrial dynamics factors to regulate reproductive aging

In a recent study published in the Developmental Cell Journal, researchers reported that reproductive aging in Caenorhabditis elegans is regulated through an interaction of the metabolism of mitochondrial guanosine-triphosphate (mGTP) and factors involved in mitochondrial dynamics.

Study: Mitochondrial GTP metabolism controls reproductive aging in C. elegans. Image Credit: Monkey Business Images/Shutterstock.com

Background

Age-associated decline in fertility, or reproductive senescence, has strong social implications as the maternal age for first-time mothers is increasing. An increase in maternal age is associated with decreasing fertility and a higher probability of miscarriages and congenital disabilities in the infant.

Moreover, research indicates that fertility decline precedes menopause by almost ten years, and degradation of oocyte quality is the chief cause of decreasing fertility.

Of all the cells in the body, oocytes have the highest number of mitochondria. Consequently, mitochondrial activity is believed to be the most important contributor to changes in oocyte quality.

Overall fertility and the development and maturation of oocytes are believed to be influenced by mitochondrial factors such as the production of adenosine triphosphate (ATP), deoxyribonucleic acid (DNA) copy number, and membrane potential.

Mitochondria also undergo dynamic morphological changes in size, shape, and distribution, with constant fission and fusion of organelles, which require specific protein machinery.

Knockout studies in mice have shown that mitochondrial dynamics regulators are essential for oocyte quality control.

About the study

In the present study, the researchers used C. elegans as a model system to understand the role of mitochondrial dynamics in reproductive aging.

Ribonucleic acid (RNA) interference (RNAi) experiments were conducted to identify reproductive aging regulators in C. elegans, with the RNAi library consisting of various RNAi clones, including those for succinyl-coenzyme A (CoA) ligase (sucl-2) and GTP-specific succinyl-CoA ligase (sucg-1).

Various studies have identified that specific protein machinery including mitochondrial fission guanosine triphosphatase (GTPase) dynamin-related protein 1 (DRP1), mitochondrial inner membrane fusion GTPase optic atrophy 1 (OPA1), and MitoFusiN 1 (MFN1) and MFN2 — mitochondrial outer membrane fusion GTPases, are required not just for the fission-fusion dynamics within the mitochondria, but also for the modulation of mitochondrial distribution within the oocyte.

Studies in murine models have indicated that knockout of Drp1, or the overexpression of Mfn1 and Mfn2 results in the accumulation of the mitochondrial network in the perinuclear region of the oocyte.

However, in C. elegans, the selective overexpression of drp-1, the DRP1 homolog, in the intestine, or the whole-body knockout of drp-1 and the homolog of MFN in C. elegans — fuzzy onions related (fzo)-1 — results in an increase in lifespan.

The study explored the role of succinyl-CoA synthetase (SCS) through a series of experiments involving the construction of plasmids through polymerase chain reaction (PCR) amplification, measurement of progeny number, reproductive lifespan assays, and late fertility assays.

They also carried out confocal imaging and fluorescent intensity profiling to localize the SUCG-1 protein in the mitochondria and analyze the mitochondrial network in the oocyte.

Droplet digital PCR and quantitative PCR methods were used to measure the levels of mitochondrial DNA in the germline. Additional parameters such as pharyngeal pumping, body length, and mitochondrial ATP and GTP in the germline were also measured.

Results

The findings indicated that SCS, a mitochondrial enzyme that plays a key role in the tricarboxylic cycle that produces ATP or GTP through converting succinyl-CoA to succinate, is a major regulator of reproductive aging.

The SCS enzyme comprises an alpha and a beta subunit, with the ATP/GTP specificity being determined using two interchangeable beta subunits that form a complex with the alpha subunit.

The RNAi screening identified the two subunits of SCS as key regulators of reproductive aging.

In the germline, the GTP-specific SCS modulated the positioning of the mitochondria in the oocyte of C. elegans, thus regulating reproductive aging.

Furthermore, selectively increasing the fission of mitochondria in the C. elegans germline prevented the accumulation of mitochondria in the perinuclear region of the oocyte, which occurs with aging, and subsequently improved reproductive longevity.

Additionally, the study found that vitamin B12 levels in bacteria impacted the modulation of reproductive aging by the factors involved in mitochondrial fission and fusion and the GTP-specific SCS.

Conclusions

To summarize, the study conducted RNAi experiments using C. elegans and reported that mitochondrial dynamics and the metabolism of mGTP controlled reproductive aging in oocytes.

Furthermore, bacterial inputs, such as vitamin B12, impact mGTP levels and further modulate the mitochondrial factors involved in reproductive aging. The findings also highlighted the potential of inducing mitochondrial fission in improving reproductive health.

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.